SUMMARY ABSTRACT Human immunodeficiency virus (HIV-1) infection has become a chronic illness after the introduction of combination antiretroviral therapy (cART). However, most antiretrovirals either do not cross the BBB or have a limited permeability. As a result, HIV-1 infection continues to exert its adverse effects on the central nervous system leading to neurocognitive dysfunctions in a significant percentage of HIV-1 infected individuals. The genetic clade that is most prevalent in India is HIV-1 clade C. The tat protein in this clade has a serine motif at C30-31 that is not neurotoxic as compared to tat containing cysteine motif in clade B. However, inflammatory cytokines produced in HIV-1 infection, irrespective of the clade types, and gp120 are known to be neurotoxic. Consequently, recent reports including from us have shown that neurocognitive dysfunctions indeed occur in clade C infected individuals in India. To fully understand the adverse effects of HIV-1 clade C infection on the brain vis--vis neurocognitive dysfunctions, it is necessary to examine the brain of clade C infected individuals. It is hypothesized that subtle parenchymal and other changes occur in the brain of individuals with HIV-1 clade C infection. Encouraged by our ongoing research collaboration with PGIMER, Chandigarh, in India and their acquisition of 3T MRI scanners, it is proposed in this application to evaluate individuals infected with HIV-1 clade C subtype using advanced brain imaging techniques. We will investigate changes in neurometabolites, tissue microstructures, and morphology at the whole-brain level in clade C infected individuals and demographically-matched local healthy normal subjects. These changes may be the underlying neural substrates causing neurocognitive deficits in a significant proportion of subjects living with clade C infection. In this 5-year cross-sectional study, we propose to enroll a total of 220 community residing subjects, men and women, age 18 to 45 years, 110 HIV+ (CD4 ?350 and cART-naive) and 151 HIV- controls. We propose to administer a standard battery of neuropsychological tests already translated into a local language (Hindi), and to use a suite of advanced MRI techniques that includes MR spectroscopic imaging and diffusion kurtosis imaging. The brain imaging data collected will allow us to evaluate differences in the tissue structure, morphology, and metabolite levels between the two groups. The metrics of this study will include N-acetyl- aspartate/creatine, choline/creatine, myo-inositol/creatine, fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis, and radial kurtosis, thickness of cortical gray matter structures, volume of gray matter and white matter sub-structures, and neurocognitive domain scores. This application will allow us to characterize tissue structural, morphological and metabolite differences in the brain of clade C infected individuals and controls using multi-modal whole-brain imaging techniques. Findings will also allow us to relate these differences to neurocognitive functions in the two groups.